Phenylthioalkylamines is a broad class of compounds having a variety of uses which include therapeutics. U.S. Pat. Nos. 4,134,996 and 4,183,927 disclose certain phenylthioalkylamine compounds which are useful as platelet aggregation inhibitors. Other phenylthioalkylamine compounds of applicant's published International application WO91/16302 are useful as depigmenting agents in treating a variety of pigmentary diseases. Such diseases are often characterized in the elevated levels of the enzyme tyrosinase in melanocytes; i.e., human and animal cells which synthesize the pigment melanin. There are a variety of pigmentary diseases, such as melasma, melanoma, moles and the like. In particular, moles are susceptible to becoming melanoma after exposure to sunlight which precipitates increased synthesis of tyrosinase.
Usually commercial forms of depigmenting compositions are based on the use of hydroquinone. However, the hydroquinone preparations are very unstable and cause skin irritation. Hydroquinone compositions can also cause permanent whitening of the skin if used for a prolonged period and at a high concentration. As to treatment of melanoma, this is presently attended to by surgical procedures, since any type of known non-surgical treatment of melanoma is unsatisfactory.
Research work has been conducted in the field of phenolic and diphenolic compounds to serve as a basis for chemotherapeutic treatment of melanoma and skin depigmentation. In particular, 4-S-cysteinylphenol (4-S-CP) and 4-S-cysteaminylphenol (4-S-CAP) have been synthesized and evaluated for cytotoxicity to normal epidermal melanocytes to determine their effectiveness as depigmenting agents and antimelanoma agents. Miura et al, "Synthesis of Cysteinylphenol, Cysteaminylphenol, and Related Compounds, and In Vivo Evaluation of Antimelanoma Effect", Arch. Dermatol Res. (1987) 279:219-225, disclose the effect of 4-S-CAP and 4-S-CP in depigmentation of black hair follicles as manifested by loss of functioning melanocytes. It was established that 4-S-CAP was a potent agent in prolonging the lifespan of melanoma-bearing mice and hence exhibited inhibition of melanoma growth. 4-S-CP and the methyl ester of 4-S-CP also exhibited some inhibition of melanoma growth, although not as active as 4-S-CAP.
The same compounds, 4-S-CP and 4-S-CAP, were also investigated for properties of depigmentation of black guinea pig skin by topical application. The results of this work is reported by Ito et al, "Depigmentation of Black Guinea Pig Skin by Topical Application of Cysteaminylphenol, Cysteinylphenol, and Related Compounds", The Journal of Investigative Dermatology, Vol. 88 No. 1, Jan. 1987. Although 4-S-CAP demonstrated depigmenting properties, inflammatory changes of the skin of the guinea pigs was prominent. 4-S-CAP was capable, however, of:
1. decreasing the number of functioning melanocytes; PA1 2. decreasing the amount of epidermal melanin pigments; and PA1 3. degenerating and destroying melanocytes. PA1 a. hypotensive effect; and PA1 b. high toxicity due to 4-S-CAP being a substrate for monoamineoxidase (MAO) which in the plasma converts 4-S-CAP into an aldehyde form which produces a non-specific cytotoxicity. PA1 R.sub.2 is H or C.sub.1 -C.sub.8 alkyl; PA1 R.sub.3 is H, C.sub.1 -C.sub.8 alkyl or C.sub.1 -C.sub.8 alkanoyl; PA1 R.sub.4 is H or C.sub.1 -C.sub.8 alkanoyl; PA1 1) Ra is covalently bound to the structure of formula (I); PA1 2) Ra is ionically associated with the structure of formula (I); or PA1 3) Ra is radioactive carbon which is part of the structure of formula (I); PA1 x is 1 to 5, PA1 i) administering to the subject's circulatory system one or more radioimaging compounds selected from the group of compounds represented by the formula: ##STR2## wherein R.sub.1 is H or C.sub.1 -C.sub.8 alkyl; PA1 R.sub.2 is H pr C.sub.1 -C.sub.8 alkyl; PA1 R.sub.3 is H, C.sub.1 -C.sub.8 alkyl or C.sub.1 -C.sub.8 alkanoyl; PA1 R.sub.4 is H or C.sub.1 -C.sub.8 alkanoyl; PA1 1) Ra is covalently bound to the structure of formula (I); PA1 2) Ra is ionically associated with the structure of formula (I); or PA1 3) Ra is radioactive carbon which is part of the structure of formula (I); PA1 x is 1 to 5, PA1 ii) detecting the presence of emitted radiation from an accumulation of said selected radioimaging compound as said administered compound binds solely to any melanoma tissue present in said subject. PA1 i) administering to the subject's circulatory system one or more of the radiochemotherapy compounds selected from the group of compounds represented by the formula: ##STR3## wherein R.sub.1 is H or C.sub.1 -C.sub.8 alkyl; PA1 R.sub.2 is H pr C.sub.1 -C.sub.8 alkyl; PA1 R.sub.3 is H, C.sub.1 -C.sub.8 alkyl or C.sub.1 -C.sub.8 alkanoyl; PA1 R.sub.4 is H or C.sub.1 -C.sub.8 alkanoyl; PA1 1) Ra is covalently bound to the structure of formula (I); PA1 2) Ra is ionically associated with the structure of formula (I); or PA1 3) Ra is radioactive carbon which is part of the structure of formula (I); PA1 x is 1 to 5, PA1 R.sub.2 is H, C.sub.1 -C.sub.8 alkyl or C.sub.1 -C.sub.8 alkanoyl; PA1 R.sub.3 is H or C.sub.1 -C.sub.8 alkyl; PA1 R.sub.4 is C.sub.1 -C.sub.8 alkanoyl; and PA1 x is 1 to 5; PA1 i) a biologically effective amount of an active compound selected from the group represented by formula (II); and PA1 ii) a suitable biologically compatible carrier for the selected active compound. PA1 i) a biologically effective amount of an active compound selected from the group represented by formula (II); and PA1 ii) a suitable biologically compatible carrier.
4-S-CP and 4-S-CAP were also investigated for their selective cytotoxicity on follicular melanocytes. This was reported by Ito et al, "Selective Cytotoxicity of 4-S-Cysteaminylphenol on Follicular Melanocyte of the Black Mouse: Rational Basis for its Application to Melanoma Chemotherapy", Cancer Research, Jun. 15, 1987 47:3278-3284. It was reported that 4-S-CAP demonstrated cytotoxicity in the depigmentation of black hair follicles, whereas it had no effect on the albino follicles. Hence 4-S-CAP is actively engaged in the melanin synthesis of the melanocytes.
4-S-CAP, however, has several limitations from the standpoint of practical clinical use. These limitations include:
Homologs of 4-S-CAP have been investigated for antimelanoma and depigmenting properties. As reported in Alena et al, Melanocytotoxicity and Antimelanoma Effects of Phenolic Amine Compounds in Mice In Vivo, Cancer Research 50:3743-3747, Jun. 15, 1990, such homologs demonstrate depigmentation properties and N-acetyl-4-S-CAP demonstrates potent antimelanoma properties. The benefits and uses of these homologs and related compounds for use as depigmenting agents and antimelanoma agents are described in applicant's published International application WO 91/16302. Although the compounds disclosed in that application are effective depigmenting agents as well as antimelanoma agents, there are stability and toxicity problems associated with some of the compounds. In particular the very effective N-acetyl-4-S-CAP compound tends to be unstable and can cause topical irritations on administration.
As noted, melanin synthesis is a biological property unique to the pigment cell, melanocyte and its neoplastic counterpart, malignant melanoma. In order to develop a targeted chemotherapy of malignant melanoma, phenolic and catecholic melanin precursors have been synthesized and their melanocytotoxicity and antimelanoma effects have been examined (Ito, Y. et al, 1987; Miura, S. et al, 1987; Alena, F. et al, 1990; Jimbow, K. et al, 1992). Among these, S-substituted phenolic amines, N-acetyl-4-S-cysteaminylphenol (N-Ac-4-S-CAP) was found to be a superior substrate of melanin synthesizing enzyme, tyrosinase (Pankovich, J. et al, 1990; Miura, T. et al, 1990), and to possess the most effective melanocytotoxic activity and antimelanoma effect (Miura, T. et al, 1990; Alena, F. et al, 1990; Wong, M. et al, 1991). 4-S-CAP was, however, as noted, above, found to have some general cytotoxicity (Alena, F. et al, 1990), because it is metabolically transformed a cytotoxic aldehyde metabolite by plasm monoamine oxidase (Pankovich, J. et al; Inoue, S. et al, 1990). On the other hand, N-Ac-4-S-CAP has shown an absence of such cytotoxicity (Alena, F. et al, 1990), indicating that N-Ac-4-S-CAP may be a compound suitable for the development of melanoma chemotherapy.
In the treatment of various pigmentary disorders, it would also be beneficial to determine the specificity of the compounds used in the treatment and in particular, compounds such as N-Ac-4-S-CAP. In this regard, we have also discovered that certain anti-melanoma and depigmenting agents can be labelled with radioactive molecules to achieve not only radioimaging but as well, radio-chemotherapy particularly in the treatment of malignant melanoma.
In accordance with this invention, we have also discovered esterified compounds which exhibit excellent stability and very low general toxicity, but have selective toxicity for melanocytes.